TRIM14 Overexpression Induces Chemoresistance and Malignant Behaviors of Hepatocellular Carcinoma Cells by Activating the STAT3/HIF-1α Pathway

Author:

Xu Weiqi12,Zhuang Lihong13,Zhu Hongxu12,Mao Anrong12,Zhou Jiamin12,Wang Lu12

Affiliation:

1. Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, China

2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

3. Qingdao Institute, Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Qingdao 266500, China

Abstract

Members of the tripartite motif (TRIM)-containing protein family have been found to be involved in the progression of hepatocellular carcinoma (HCC). TRIM14 exerts a promotive impact on several cancers. This study aimed to explore the function and mechanism of TRIM14 in HCC. TRIM14 expression in HCC tissues and HCC cell lines was detected. The overexpression or knockdown model of TRIM14 was established in HCC cell lines. Cell Counting Kit-8 (CCK-8) assay, flow cytometry, Transwell assay, RT-PCR, Western blot, and immunofluorescence were performed to verify the influence of TRIM14 on cell proliferation, sensitivity to chemotherapy drugs, apoptosis, migration, invasion, and autophagy. A xenograft tumor model was used to confirm the impact of TRIM14 on tumor cell growth. As shown by the data, TRIM14 level was notably higher in the tumor tissues of HCC patients than in the adjacent tissues. The overall survival rate of patients with a high TRIM14 expression was relatively lower than that of patients with a low TRIM14 expression. TRIM14 upregulation enhanced the proliferation, autophagy, migration, and invasion of HCC cells and chemoresistant HCC cells and decreased apoptosis. TRIM14 knockdown contributed to the opposite effects. In in vivo experiments, TRIM14 upregulation bolstered tumor growth. Western blot analysis revealed that TRIM14 upregulation boosted signal transducer and activator of transcription3 (STAT3) and hypoxia-inducible factor-1alpha (HIF-1α) expression, and TRIM14 knockdown suppressed their expression. Moreover, repressing STAT3 and HIF-1α could mitigate the tumor-promoting role of TRIM14 in HCC cells. Overall, TRIM14 facilitated malignant HCC development and induced chemoresistance in HCC cells by activating the STAT3/HIF-1α axis.

Funder

National Natural Science Foundation of China

Shanghai Pujiang Program

Shenkang Three-year Clinical Research Foundation

Shenkang Clinical Research Cultivation Program

Shanghai Anti-Cancer Association Soar Program

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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